CYP7B1 Mutations in French-Canadian Hereditary Spastic Paraplegia Subjects

Noreau, Anne; Szuto, Anna; Levert, Annie; Thibodeau, Pascale; Brais, Bernard; Dupré, Nicolas; Rioux, Marie-France; Rouleau, Guy A.

doi:10.1017/s0317167100012774

Cited by 4 publications

(1 citation statement)

References 6 publications

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“…SPG5 is an ultra-rare disease with an estimated prevalence of about 1:1 000 000 (Schule et al, 2016) and a total number of 56 published families (Tsaousidou et al, 2008;Biancheri et al, 2009;Criscuolo et al, 2009;Goizet et al, 2009;Schule et al, 2009;Cao et al, 2011;Schlipf et al, 2011;Arnoldi et al, 2012;Noreau et al, 2012;Kumar et al, 2013;Roos et al, 2013;Di Fabio et al, 2014;Lan et al, 2015). Multiple factors, including low public awareness for the disease, small numbers of patients available for clinical trials and limited market size, impede development of disease-specific therapies.…”

Section: Discussionmentioning

confidence: 99%

Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial

Schöls

Rattay

Martus

et al. 2017

Brain

117

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Spastic paraplegia type 5 (SPG5) is a rare subtype of hereditary spastic paraplegia, a highly heterogeneous group of neurodegenerative disorders defined by progressive neurodegeneration of the corticospinal tract motor neurons. SPG5 is caused by recessive mutations in the gene CYP7B1 encoding oxysterol-7α-hydroxylase. This enzyme is involved in the degradation of cholesterol into primary bile acids. CYP7B1 deficiency has been shown to lead to accumulation of neurotoxic oxysterols. In this multicentre study, we have performed detailed clinical and biochemical analysis in 34 genetically confirmed SPG5 cases from 28 families, studied dose-dependent neurotoxicity of oxysterols in human cortical neurons and performed a randomized placebo-controlled double blind interventional trial targeting oxysterol accumulation in serum of SPG5 patients. Clinically, SPG5 manifested in childhood or adolescence (median 13 years). Gait ataxia was a common feature. SPG5 patients lost the ability to walk independently after a median disease duration of 23 years and became wheelchair dependent after a median 33 years. The overall cross-sectional progression rate of 0.56 points on the Spastic Paraplegia Rating Scale per year was slightly lower than the longitudinal progression rate of 0.80 points per year. Biochemically, marked accumulation of CYP7B1 substrates including 27-hydroxycholesterol was confirmed in serum (n = 19) and cerebrospinal fluid (n = 17) of SPG5 patients. Moreover, 27-hydroxycholesterol levels in serum correlated with disease severity and disease duration. Oxysterols were found to impair metabolic activity and viability of human cortical neurons at concentrations found in SPG5 patients, indicating that elevated levels of oxysterols might be key pathogenic factors in SPG5. We thus performed a randomized placebo-controlled trial (EudraCT 2015-000978-35) with atorvastatin 40 mg/day for 9 weeks in 14 SPG5 patients with 27-hydroxycholesterol levels in serum as the primary outcome measure. Atorvastatin, but not placebo, reduced serum 27-hydroxycholesterol from 853 ng/ml [interquartile range (IQR) 683-1113] to 641 (IQR 507-694) (-31.5%, P = 0.001, Mann-Whitney U-test). Similarly, 25-hydroxycholesterol levels in serum were reduced. In cerebrospinal fluid 27-hydroxycholesterol was reduced by 8.4% but this did not significantly differ from placebo. As expected, no effects were seen on clinical outcome parameters in this short-term trial. In this study, we define the mutational and phenotypic spectrum of SPG5, examine the correlation of disease severity and progression with oxysterol concentrations, and demonstrate in a randomized controlled trial that atorvastatin treatment can effectively lower 27-hydroxycholesterol levels in serum of SPG5 patients. We thus demonstrate the first causal treatment strategy in hereditary spastic paraplegia.

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Section: Discussionmentioning

confidence: 99%

Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial

Schöls

Rattay

Martus

et al. 2017

Brain

117

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Human Cytochrome P450 Enzymes

Guengerich

2015

Cytochrome P450

132

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Autosomal recessive hereditary spastic paraplegia—clinical and genetic characteristics of a well-defined cohort

et al. 2013

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We describe the clinical and genetic features of a well-characterized cohort of patients with autosomal recessive hereditary spastic paraplegia (ARHSP) in the province of Ontario. Patients with documented corticospinal tract abnormalities were screened by whole gene sequencing and multiplex ligation probe amplification for mutations in nine genes known to cause ARHSP. Of a cohort of 39 patients, a genetic diagnosis was established in 17 (44 %) and heterozygous mutations were detected in 8 (21 %). Mutations were most frequent in SPG7 (12 patients), followed by SPG11 (10 patients), PNPLA6 (SPG39, 2 patients), and ZFYVE26 (SPG15, 2 patients). Although there are associations between some clinical manifestations of ARHSP and specific genes, many patients are tested at an early stage of the disease when phenotype/genotype correlations are not obvious. Accurate molecular characterization of well-phenotyped cohorts of patients will be essential to establishing the natural history of these rare degenerative disorders to enable future clinical trials.

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CYP7B1 Mutations in French-Canadian Hereditary Spastic Paraplegia Subjects

Cited by 4 publications

References 6 publications

Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial

Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial

Human Cytochrome P450 Enzymes

Autosomal recessive hereditary spastic paraplegia—clinical and genetic characteristics of a well-defined cohort

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